Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency.

Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient's cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient's cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV.

Cartoons to improve young children's cooperation with inhaled corticosteroids: A preliminary study.

INTRODUCTION: The objective of this pilot study was to evaluate if animated cartoons could increase the cooperation of young children with asthma during the delivery of their inhaled corticosteroids (ICS). METHODS: Subjects were children aged 6-47 months having a physician diagnosis of asthma, who required an ICS therapy delivered through a pMDI/spacer twice a day for at least 2 months. Families who reported on a questionnaire that their child was frequently crying or moving during treatment delivery were asked to participate in a prospective, cross-over, randomized study. After a first week of run-in, children watched alternatively, during the delivery of ICS, either an animated cartoon for 7 days and a black screen video for another 7 days. The main outcome was the median percentage of time of non-cooperation, defined by the length of time the child was crying and/or moving divided by the length of time required for delivering ICS. RESULTS: Parents of 50 children out of 113 (44%) reported that their child was frequently crying or moving during treatment delivery. Among these 50 children, 11 (22%) completed the study. The median percentages of time of non-cooperation (IQR 1-3) were 0% (0-3) and 56% (40-97) during the distraction and control periods, respectively, in the first group, and 100% (98-100) and 0% (0-5) during the control and distraction periods, respectively, in the second group. Animated cartoons increased cooperation up to 97% (55-100%) (P = 0.008). CONCLUSIONS: Bad cooperation among young children with asthma during the delivery of their treatment can be dramatically improved by the use of animated cartoons.

Respiratory Morbidity in Infants Born With a Congenital Lung Malformation.

BACKGROUND AND OBJECTIVES: The actual frequency of respiratory symptoms related to congenital pulmonary malformations (CPMs) remains undetermined. The goal of this study was to prospectively evaluate the respiratory symptoms occurring in infants with prenatally diagnosed CPMs, identify factors associated with the occurrence of these symptoms, and evaluate their resolution after surgery. METHODS: Infectious and noninfectious respiratory symptoms were prospectively collected in a French multicenter cohort of children with CPMs. RESULTS: Eighty-five children were followed up to the mean age of 2.1 ± 0.4 years. Six children (7%) underwent surgery during the first 28 days of life. Of the 79 remaining children, 33 (42%) had respiratory symptoms during infancy before any surgery. Wheezing was the dominant symptom (24 of 79 [30%]), and only 1 infant had documented infection of the cystic lobe. Symptoms were more frequent in children with noncystic CPMs, prenatally (P = .01) or postnatally (P < .03), and with postnatally hyperlucent CPMs (P < .01). Sixty-six children underwent surgery during the follow-up period, and 40% of them displayed symptoms after the intervention. Six children had documented pneumonia during the postoperative period. At the end of the follow-up, pectus excavatum was observed in 10 children, significantly associated with thoracotomy (P < .02) or with surgery before the age of 6 months (P < .002). CONCLUSIONS: CPMs are frequently associated with wheezing episodes. Surgery had no significant impact on these symptoms but was associated with a paradoxical increase in pulmonary infections, as well as an increased risk of pectus excavatum after thoracotomy.

Neonatal outcomes of prenatally diagnosed congenital pulmonary malformations.

BACKGROUND AND OBJECTIVE: Congenital pulmonary malformations (CPM) are mostly recognized on prenatal ultrasound scans. In a minority of cases, they may impair breathing at birth. The factors predictive of neonatal respiratory distress are not well defined, but an understanding of these factors is essential for decisions concerning the need for the delivery to take place in a tertiary care center. The aim of this study was to identify potential predictors of respiratory distress in neonates with CPM. METHODS: We selected cases of prenatal diagnosis of hyperechoic and/or cystic lung lesions from RespiRare, the French prospective multicenter registry for liveborn children with rare respiratory diseases (2008-2013). Prenatal parameters were correlated with neonatal respiratory outcome. RESULTS: Data were analyzed for 89 children, 22 (25%) of whom had abnormal breathing at birth. Severe respiratory distress, requiring oxygen supplementation or ventilatory support, was observed in 12 neonates (13%). Respiratory distress at birth was significantly associated with the following prenatal parameters: mediastinal shift (P = .0003), polyhydramnios (P = .05), ascites (P = .0005), maximum prenatal malformation area (P = .001), and maximum congenital pulmonary malformation volume ratio (CVR) (P = .001). Severe respiratory distress, requiring oxygen at birth, was best predicted by polyhydramnios, ascites, or a CVR >0.84. CONCLUSIONS: CVR >0.84, polyhydramnios, and ascites increased the risk of respiratory complications at birth in fetuses with CPM, and especially of severe respiratory distress, requiring oxygen supplementation or more intensive intervention. In such situations, the delivery should take place in a tertiary care center.

[Quality of life, asthma control, urinary cotinine and therapeutic education among asthmatic children]. / Qualité de vie, contrôle de l'asthme, cotininurie et éducation thérapeutique de l'enfant asthmatique.

Therapeutic patient education (TPE) has been standard practice in France for roughly 20 years. However, TPE has only recently been officially recognized and has rarely been assessed. The objective of this study was to assess the impact of TPE on passive smoking exposure and asthma outcomes in young patients referred to a hospital school for children with asthma. A prospective cohort study was conducted to determine the socio-economic status, environmental exposure (including parental tobacco consumption) and medical history of children starting out on a TPE course. The study measured quality of life and urinary cotinine. Asthma control was also assessed. Out of a total of 54 children (median age 8.6 years), 35 and 26 children attended three or at least four TPE sessions, respectively. Uncontrolled asthma and a history of hospitalization for exacerbation of asthma were frequent (43% and 61%, respectively). In utero passive smoke exposure was more frequent in the hospitalization group (p = 0.07). Urinary cotinine levels were similar in children exposed and not exposed to tobacco smoke (259 vs 141 nMol.L-1, p = 0.15), but only decreased in the group of exposed children. In 34 children, quality of life improved significantly between the first and the third or fourth sessions (n = 23, median increase 1.06, p = 0.1), while asthma control improved in 64% of the patients (n = 33, p = 0.01) and emergency attendances decreased (n = 34, p = 0.001). The positive effects of TPE on asthma control and quality of life were quickly visible but did not prevent children from withdrawing from the program. Urinary cotinine was not useful for detecting exposure to tobacco smoke, but may be useful as an indicator of exposure to tobacco smoke. The results indicate an improvement in quality of life and asthma control as TPE proceeded.

Influenza-like illness responsible for severe exacerbations in asthmatic children during H1N1 pandemic: a survey before vaccination.

BACKGROUND: Asthma seems to be the more prevalent underlying condition in patients hospitalized for H1N1-related flu. METHODS: A prospective survey was conducted during the early phase of H1N1 pandemic in France in asthmatic children before vaccination to assess whether severe exacerbations in childhood asthma are associated with influenza-like illness (ILI, the definition of H1N1-related flu in a pandemic). Eight pediatricians in primary care distributed in three localities (Paris, south suburb, and west suburb) conducted the survey (4 weeks/locality from week 36 to 47). At each visit, the pediatrician filled a questionnaire entering the information regarding asthma treatment, severe exacerbation (at least 3 days' use of systemic corticosteroids), and ILI (temperature ≥37.8°C, cough, and/or sore throat, in the absence of a known cause other than influenza) during the past 3 weeks. RESULTS: The survey included 1155 asthmatic children (mean age [SD]: 7.5 years [4.1]); almost all visits were scheduled (99%). A severe exacerbation was recorded in 121 children [10.5%; 95% confidence interval (CI): 8.7-12.2%], which was concomitant with ILI in 20 children (16.5%; 95% CI: 9.9-23.2%), whereas 1034 children did not exhibit any exacerbation. In these latter children, 40 ILI were observed (3.9%; 95% CI: 2.7-5.0%), which constituted a significantly lesser percentage as compared with children with both exacerbation and ILI (p < .0001). This result remained significant in each locality. Overall, 60/1155 (5.2%; 95% CI: 3.9-6.5%) asthmatic children had an ILI. CONCLUSIONS: Our survey shows that severe exacerbation and ILI are strongly associated during the H1N1 pandemic in asthmatic children.

Randomized study of the effect of topical anesthesia on tuberculin skin test reaction size in children.

Tuberculin skin test (TST) application in children can be eased by topical anesthesia, but no study has determined whether lidocaine-prilocaine mixture application modifies TST skin reactions. We compared TST performed with and without topical anesthesia in 46 children (range, 0.4-15.9 years), and found that topical lidocaine-prilocaine did not affect the TST size reaction. Topical lidocaine-prilocaine can be used for TST.

Bilateral adrenal neuroblastoma and nephroblastoma occurring synchronously in a child with Fanconi's anemia and VACTERL syndrome.

Fanconi's anemia (FA) is an autosomal recessive inherited syndrome with a predisposition to malignancy. The association between FA and solid pediatric tumors is extremely rare. The authors report a rare case of VACTERL syndrome associated with FA and multiple solid pediatric tumors occurring in a very young girl. This child had numerous congenital anomalies (horseshoe kidney, cerebella hypoplasia, microcephaly, sacral agenesis) and esophageal atresia, which was repaired in neonatal period. Such association led quickly to the diagnosis of FA. At age of 11 months, she developed simultaneously a renal tumor in a horseshoe kidney and bilateral adrenal tumors. The left adrenal mass was removed, and partial nephrectomy was performed. Histological analysis concluded to adrenal neuroblastoma and nephroblastoma. We also evaluated the c-kit expression in these tumors to propose a therapeutic alternative to chemotherapy by oral agent STI-571 (Gleevec; Novartis, East Hanover, NJ). Strong cytoplasmic immunostaining of c-kit was found in both tumors. Unfortunately, she quickly developed a posterior cerebellar fossa tumor and died 1 month later. This clinical situation is very rare but suggests that young patients with FA and solid pediatric tumors may belong to a particular subgroup of FA. Further studies are necessary to test if STI-571 treatment could be efficient in such patients with pediatric tumors.